Aralkyl-4H-1,2,4-triazole derivatives

ABSTRACT

The invention relates to aralkyl-4H-1,2,4-triazole derivatives, especially 5-phenyl-lower alkyl-4H-1,2,4-triazole-3-carboxamides of the formula ##STR1## in which Ph represents phenyl substituted by lower alkyl, halogen and/or by trifluoromethyl, alky represents lower alkylidene, R 1  is hydrogen or lower alkyl, and R 2  represents carbamoyl that is unsubstituted or is substituted by lower alkyl or by lower alkanoyl, and their salts and, as the case may be, their tautomers and the salts thereof. These compounds can be used as anti-convulsive pharmaceutical active ingredients.

This application is a continuation, of application Ser. No. 333,378,filed Apr. 5, 1989 which in turn is a continuation-in-part ofapplication Ser. No. 290,817, filed Dec. 22, 1988, which in turn is acontinuation of application Ser. No. 103,147, filed Oct. 1, 1987 nowabandoned.

The invention relates to novel anti-convulsively active pharmaceuticalpreparations containing as active ingredient anaralkyl-4H-1,2,4-triazole derivative, especially a 5-phenyl-loweralkyl-4H-1,2,4-triazole-3-carboxamide of the formula ##STR2## in whichPh represents phenyl substituted by lower alkyl, halogen and/or bytrifluoromethyl, alk represents lower alkylidene, R₁ is hydrogen orlower alkyl, and R₂ represents carbamoyl that is unsubstituted or issubstituted by lower alkyl or by lower alkanoyl, or, as the case may be,a tautomer and/or a pharmaceutically acceptable salt thereof, to the useof said compounds of the formula I, or, as the case may be, theirtautomers and/or their pharmaceutically acceptable salts, for themanufacture of anti-convulsively active pharmaceutical preparations, toa method for the treatment of convulsions of various origins,characterised in that one of said compounds of the formula I, or, as thecase may be, a tautomer and/or a pharmaceutically acceptable saltthereof, is administered, and to novel 5-phenyl-loweralkyl-4H-1,2,4-triazole-3-carboxamides of the formula I in which Phrepresents phenyl substituted by lower alkyl, halogen and/or bytrifluoromethyl, alk represents lower alkylidene, R₁ is hydrogen orlower alkyl, and R₂ represents carbamoyl that is unsubstituted or issubstituted by lower alkyl or by lower alkanoyl, with the proviso that,in compounds of the formula I in which R₁ represents methyl, R₂represents N,N-diethylcarbamoyl and alk represents methylene, Ph isother than phenyl substituted in the p-position by chlorine, for examplethose novel 5-phenyl-lower alkyl-4H-1,2,4-triazole-3-carboxamides of theformula I in which Ph is other than phenyl mono-substituted by halogen,especially by chlorine, when R₂ represents N,N-di-C₁ -C₄ -alkylcarbamoylin which the two N-alkyl groups are identical or different, and theirsalts in each case and also, as the case may be, their tautomers in eachcase and the salts thereof, and to a process for the manufacture of thelast-mentioned, novel compounds of the formula I or their tautomersand/or salts.

The phenyl radical Ph contains, for example, up to and including 3,especially 1 or 2, of the mentioned substituents, preferably 1 loweralkyl, trifluoromethyl or halogen substituent or 2 or 3 halogensubstituents, or 1 lower alkyl and 1 halogen substituent or 1trifluoromethyl and 1 halogen substituent, it being preferable for atleast one of the lower alkyl and/or halogen substituents to be bonded inan o-position or for a trifluoromethyl radical to be bonded in am-position. Examples that may be mentioned are: o-halophenyl,m-trifluoromethylphenyl, 2,6- and 2,5-dihalophenyl, or 2,3- and2,4-dihalophenyl, and o-lower alkylphenyl.

Carbamoyl R₂ which is unsubstituted or is substituted by lower alkyl orby lower alkanoyl is, for example, carbamoyl or, secondly, N-loweralkyl-, N,N-di-lower alkyl- or N-lower alkanoyl-carbamoyl.

Tautomeric forms of compounds of the formula I can exist when R₁represents hydrogen. The corresponding 4H-1,2,4-triazole compounds ofthe formula ##STR3## can in that case be in equilibrium with their1H-1,2,4-triazole tautomers of the formulae ##STR4## compounds of thattype seeming to have predominantly, as far as that is known, thestructure Ia.

The compounds of the formula I and, as the case may be, the tautomersthereof may also be in the form of stereoisomers. If, for example, thelower alkylidene group alk or a lower alkyl group (as substituent of Phor in a substituted carbamoyl group R₂) has a chiral carbon atom(C-atom), the compounds of the formula I may be in the form of pureenantiomers or mixtures of enantiomers, such as racemates, or if thereis, in addition, at least one further chiral centre within theabove-mentioned groups, they may also be in the form ofdiastereoisomers, mixtures of diastereoisomers or mixtures of racemates.

Salts of compounds of the formula I or, as the case may be, of thetautomers thereof are especially corresponding acid addition salts,preferably pharmaceutically acceptable acid addition salts. These areformed, for example, with strong inorganic acids, such as mineral acids,for example sulphuric acid, a phosphoric acid or a hydrohalic acid, withstrong carboxylic acids, such as lower alkanecarboxylic acids, forexample acetic acid, optionally unsaturated dicarboxylic acids, forexample malonic acid, maleic acid or fumaric acid, or hydroxycarboxylicacids, for example tartaric or citric acid, or with organic sulphonicacids, such as lower alkanesulphonic acids or unsubstituted orsubstituted benzenesulphonic acids, for example methane- orp-toluene-sulphonic acid. Also included are salts that are unsuitablefor pharmaceutical applications, since these can be used, for example,for the isolation and/or purification of free compounds of the formula Iand, as the case may be, their tautomers and/or pharmaceuticallyacceptable salts.

Hereinbefore and hereinafter, unless defined otherwise, organic groupsand compounds referred to as "lower" are preferably to be understood asbeing those containing up to and including 7, especially up to andincluding 4, C-atoms.

Lower alkyl is, for example, C₁ -C₄ -alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl or tert.-butyl, butmay also be a C₅ -C₇ -alkyl group, i.e. a pentyl, hexyl or heptyl group.

Halogen is, for example, halogen having an atomic number of up to andincluding 35, such as fluorine or chlorine, or secondly bromine.

Lower alkylidene is, for example, C₁ -C₄ -alkylidene, especially 1,1-C₁-C₄ -alkylidene, such as methylene or ethylidene, or 1,1-propylidene or1,1-butylidene, but may also be 2,2-C₃ -C₄ -alkylidene, such as2,2-propylidene (isopropylidene) or 2,2-butylidene.

N-lower alkylcarbamoyl is, for example, N-C₁ -C₇ -alkylcarbamoyl,especially N-C₁ -C₄ -alkylcarbamoyl, such as N-methyl-, N-ethyl-,N-(n-propyl)-, N-isopropyl-, N-(n-butyl)-, N-isobutyl-, N-sec.-butyl- orN-tert.-butyl-carbamoyl.

N,N-di-lower alkylcarbamoyl is, for example, N,N-di-C₁ -C₄-alkylcarbamoyl, wherein the two N-alkyl groups can in each case beidentical or different, such as N,N-dimethyl-, N,N-diethyl-,N,N-diisopropyl- or N-butyl-N-methyl-carbamoyl.

N-lower alkanoylcarbamoyl is, for example, N-C₂ -C₇ -alkanoylcarbamoyl,especially N-C₂ -C₄ -alkanoylcarbamoyl, such as N-acetyl-, N-propionyl-or N-butyryl-carbamoyl, but may also be N-formylcarbamoyl or N-C₅ -C₇-alkanoylcarbamoyl, such as N-pivaloylcarbamoyl.

The compounds of the formula I and, as the case may be, the tautomersand/or the pharmaceutically acceptable salts thereof have valuablepharmacological properties, especially a pronounced anti-convulsiveactivity which can be demonstrated, for example, in mice by a markedmetrazole antagonism in a dosage range of about 10 mg/kg and above p.o.,and in mice and rats by a pronounced protective action againstconvulsions triggered by electric shock, in a dosage range of about 4mg/kg and above p.o.. The compounds of the formula I and, as the casemay be, the tautomers and/or the pharmaceutically acceptable saltsthereof are accordingly outstandingly suitable for the treatment ofconvulsions of various origins, for example for the treatment ofepilepsy. They can accordingly be used as anti-convulsive, for exampleanti-epileptic, active ingredients in medicaments. The commercialformulation of the active ingredients can also be included.

The invention relates especially to pharmaceutical, especiallyanti-convulsively active, preparations, to the manufacture thereof andto a method of treatment, characterised in that a compound of theformula I in which Ph represents phenyl mono-, di- or trisubstituted bylower alkyl, halogen and/or by trifluoromethyl, alk represents loweralkylidene, R₁ is hydrogen or lower alkyl, and R₂ represents carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or N-loweralkanoylcarbamoyl, preferably such a compound of the formula I in whichPh carries at least one of the lower alkyl and/or halogen substituentsin an o-position or a trifluoromethyl substituent in a m-position, or,as the case may be, a tautomer and/or a pharmaceutically acceptable saltthereof, is selected as active ingredient, and to a compound of theformula I in which Ph represents phenyl mono-, di- or tri-substituted bylower alkyl, halogen and/or by trifluoromethyl, alk represents loweralkylidene, R₁ is hydrogen or lower alkyl, and R₂ represents carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or N-loweralkanoylcarbamoyl, preferably such a compound of the formula I in whichPh carries at least one of the lower alkyl and/or halogen substituentsin an o-position or a trifluoromethyl substituent in a m-position, withthe proviso that, in a compound of the formula I in which R₁ representsmethyl, R₂ represents N,N-diethylcarbamoyl and alk represents methylene,Ph is other than phenyl substituted in the p-position by chlorine, forexample such a compound of the formula I in which Ph is other thanphenyl monosubstituted by halogen, especially by chlorine, when R₂represents N,N-di-C₁ -C₄ -alkylcarbamoyl in which the two N-alkyl groupsare identical or different, and its salts in each case and also, as thecase may be, its tautomers in each case and the salts thereof, and to aprocess for the manufacture of the last-mentioned, novel compounds ofthe formula I or their tautomers and/or salts.

The invention relates more especially to pharmaceutical, especiallyanti-convulsively active, preparations, to the manufacture thereof andto a method of treatment, characterised in that a compound of theformula I in which Ph represents phenyl mono-substituted by C₁ -C₄-alkyl, halogen or by trifluoromethyl or di-substituted by halogen, byhalogen and C₁ -C₄ -alkyl, or by halogen and trifluoromethyl, wherein C₁-C₄ -alkyl in each case represents, for example, methyl and halogen ineach case has an atomic number of up to and including 35 and is,independently of any other, for example, fluorine or secondly chlorine,alk represents 1,1- or 2,2-C₁ -C₄ -alkylidene, such as methylene orethylidene, R₁ is hydrogen or C₁ -C₄ -alkyl, such as methyl or ethyl,and R₂ represents carbamoyl, N-C₁ -C₄ -alkylcarbamoyl, such as N-methyl-or N-ethyl-carbamoyl, N,N-di-C₁ -C₄ -alkylcarbamoyl, such asN,N-dimethylcarbamoyl, or N-C₂ -C₇ -alkanoylcarbamoyl, such asN-acetylcarbamoyl, preferably such a compound of the formula I in whichPh carries at least one of the lower alkyl and/or halogen substituentsin an o-position or a trifluoromethyl substituent in a m-position, or,as the case may be, a tautomer and/or a pharmaceutically acceptable saltthereof, is selected as active ingredient, and to a compound of theformula I in which Ph represents phenyl mono-substituted by C₁ -C₄-alkyl, halogen or by trifluoromethyl or di-substituted by halogen, byhalogen and C₁ -C₄ -alkyl, or by halogen and trifluoromethyl, wherein C₁-C₄ -alkyl in each case represents, for example, methyl and halogen ineach case has an atomic number of up to and including 35 and is,independently of any other, for example, fluorine or secondly chlorine,alk represents 1,1- or 2,2-C₁ -C₄ -alkylidene, such as methylene orethylidene, R₁ is hydrogen or C₁ -C₄ -alkyl, such as methyl or ethyl,and R₂ represents carbamoyl, N-C₁ -C₄ -alkylcarbamoyl, such as N-methyl-or N-ethyl-carbamoyl, N,N-di-C₁ -C₄ -alkylcarbamoyl, such asN,N-dimethylcarbamoyl, or N-C₂ -C₇ -alkanoylcarbamoyl, such asN-acetylcarbamoyl, preferably such a compound of the formula I in whichPh carries at least one of the lower alkyl and/or halogen substituentsin an o-position or a trifluoromethyl substituent in a m-position, withthe proviso that, in a compound of the formula I in which R₁ representsmethyl, R₂ represents N,N-diethylcarbamoyl and alk represents methylene,Ph is other than phenyl substituted in the p-position by chlorine, forexample such a compound of the formula I in which Ph is other thanphenyl mono-substituted by halogen, especially by chlorine, when R₂represents N,N-di-C₁ -C₄ -alkylcarbamoyl in which the two N-alkyl groupsare identical or different, and in each case its salts and, as the casemay be, in each case its tautomers and the salts thereof, and to aprocess for the manufacture of the last-mentioned, novel compounds ofthe formula I or their tautomers and/or salts.

The invention relates preferably to pharmaceutical, especiallyanti-convulsively active, preparations, to the manufacture thereof andto a method of treatment, characterised in that a compound of theformula I in which Ph represents o-C₁ -C₄ -alkylphenyl,m-trifluoromethylphenyl, o-halophenyl or 2,5- or 2,6-dihalophenyl, or2,3- or 2,4-dihalophenyl, wherein C₁ -C₄ -alkyl represents, for example,methyl and halogen in each case has an atomic number of up to andincluding 35 and is, independently of any other, for example, fluorineor secondly chlorine, alk represents 1,1-C₁ -C₄ -alkylidene, such asmethylene or ethylidene, R₁ is hydrogen or C₁ -C₄ -alkyl, such as methylor ethyl, and R₂ represents carbamoyl or secondly N-C₁ -C₄-alkylcarbamoyl, such as N-methyl- or N-ethyl-carbamoyl, N,N-di-C₁ -C₄-alkylcarbamoyl, such as N,N-dimethylcarbamoyl, or N-C₂ -C₇-alkanoylcarbamoyl, such as N-acetylcarbamoyl, or, as the case may be, atautomer and/or a pharmaceutically acceptable salt thereof, is selectedas active ingredient, and to a compound of the formula I in which Phrepresents o-C₁ -C₄ -alkylphenyl, m-trifluoromethylphenyl, o-halophenylor 2,5- or 2,6-dihalophenyl, or 2,3- or 2,4-dihalophenyl, wherein C₁ -C₄-alkyl represents, for example, methyl and halogen in each case has anatomic number of up to and including 35 and is, independently of anyother, for example, fluorine or secondly chlorine, alk represents 1,1-C₁-C₄ -alkylidene, such as methylene or ethylidene, R₁ is hydrogen or C₁-C₄ -alkyl, such as methyl or ethyl, and R₂ represents carbamoyl orsecondly N-C₁ -C₄ -alkylcarbamoyl, such as N-methyl- orN-ethyl-carbamoyl, N,N-di-C₁ -C₄ -alkylcarbamoyl, such asN,N-dimethylcarbamoyl, or N-C₂ -C₇ -alkanoylcarbamoyl, such asN-acetylcarbamoyl, with the proviso that, in a compound of the formula Iin which R₁ represents methyl, R₂ represents N,N-diethylcarbamoyl andalk represents methylene, Ph is other than phenyl substituted in thep-position by chlorine, for example such a compound of the formula I inwhich Ph is other than phenyl monosubstituted by halogen, especially bychlorine, when R₂ represents N,N-di-C₁ -C₄ -alkylcarbamoyl in which thetwo N-alkyl groups are identical or different, and in each case itssalts and, as the case may be, in each case its tautomers and the saltsthereof, and to a process for the manufacture of the last-mentioned,novel compounds of the formula I or their tautomers and/or salts.

The invention relates especially to pharmaceutical, especiallyanti-convulsively active, preparations, to the manufacture thereof andto a method of treatment, characterised in that a compound of theformula I in which Ph represents m-trifluoromethylphenyl, o-fluorophenylor 2,6-difluorophenyl, alk represents methylene, R₁ is C₁ -C₄ -alkyl,such as methyl or ethyl, and R₂ represents carbamoyl, or apharmaceutically acceptable salt thereof, is selected as activeingredient, and to a compound of the formula I in which Ph representsm-trifluoromethylphenyl, o-fluorophenyl or 2,6-difluorophenyl, alkrepresents methylene, R₁ is C₁ -C₄ -alkyl, such as methyl or ethyl, andR₂ represents carbamoyl, and its salts, and to a process for themanufacture of the last-mentioned, novel compounds of the formula I ortheir salts.

The invention relates most especially to pharmaceutical, especiallyanti-convulsively active, preparations, to the manufacture thereof andto a method of treatment, characterised in that a compound of theformula I in which Ph represents m-trifluoromethylphenyl or2,6-difluorophenyl, alk represents methylene, R₁ is C₁ -C₄ -alkyl, suchas methyl, and R₂ represents carbamoyl, or a pharmaceutically acceptablesalt thereof, is selected as active ingredient, and to a compound of theformula I in which Ph represents m-trifluoromethylphenyl or2,6-difluorophenyl, alk represents methylene, R₁ is C₁ -C₄ -alkyl, suchas methyl, and R₂ represents carbamoyl, and its salts, and to a processfor the manufacture of the last-mentioned, novel compounds of theformula I or their salts.

The invention relates specifically to pharmaceutical, especiallyanti-convulsively active, preparations, to the manufacture thereof andto a method of treatment, characterised in that one of the novelcompounds of the formula I mentioned in the Examples, or, as the casemay be, a tautomer and/or a pharmaceutically acceptable salt thereof, isselected as active ingredient, and to the novel compounds of the formulaI mentioned in the Examples and their salts and, as the case may be,their tautomers and the salts thereof, and to a process for themanufacture of the last-mentioned, novel compounds of the formula I ortheir tautomers and/or salts.

The process according to the invention for the manufacture of the novelcompounds of the formula I or, as the case may be, their tautomersand/or salts is based on procedures that are known per se. It ischaracterised, for example, in that

a) X₁ and X₂ are eliminated from a compound of the formula ##STR5## inwhich X₁ and X₂ represent groups that can be eliminated with theformation of an additional bond, and one of the two radicals R_(a) andR_(b) is a group Ph-alk and the other is a radical R₂, or, as the casemay be, from a tautomer and/or salt thereof, or

b) in a compound of the formula ##STR6## in which R₂ ' represents agroup that can be converted into a radical R₂, or, as the case may be,in a tautomer and/or salt thereof, R₂ ' is converted into R₂, or

c) for the manufacture of a compound of the formula I in which R₁ isother than hydrogen and R₂ is especially N,N-di-lower alkylcarbamoyl,the radical of the formula Ph-alk is introduced into a compound of theformula ##STR7## or into a salt thereof, or

d) for the manufacture of a compound of the formula I in which R₁ ishydrogen, in a compound of the formula ##STR8## in which R₁ ',represents a group that can be replaced by hydrogen, or in a saltthereof, R₁ ' is replaced by hydrogen, or

e) for the manufacture of a compound of the formula I in which R₂ isN,N-di-lower alkylcarbamoyl, in a compound of the formula ##STR9## inwhich alk' represents a radical that can be converted into a group alk,or, as the case may be, in a tautomer and/or salt thereof, alk' isconverted into alk, and a mixture of isomers which may be obtained inaccordance with the process in each variant is separated into itscomponents and the isomer of the formula I is isolated, if desired acompound obtained in each variant in accordance with the process or byother means is converted into a different compound of the formula I, amixture of stereoisomers which may be obtained in accordance with theprocess in each variant is separated into the stereoisomers and thedesired stereoisomer is isolated, a free compound of the formula Iobtained in accordance with the process in each variant is convertedinto a salt and/or a salt obtained in accordance with the process ineach variant is converted into the free compound of the formula I orinto a different salt.

The reactions described hereinbefore and hereinafter in the variants andthe manufacture of novel starting materials and intermediates arecarried out analogously to procedures for the reaction and formation ofknown starting materials and intermediates. The reactions are carriedout, even when this is not expressly mentioned hereinbelow, under thereaction conditions, such as temperature and pressure conditions, thatare customary in each case, and using the adjuncts, such as catalysts,condensation agents and solvolysing agents, that are customary in eachcase, and/or using suitable solvents or diluents or a mixture thereof,and, where appropriate, under a protective gas, in a closed vesseland/or under anhydrous conditions.

In the compounds II that are to be used for process variant a), X₁represents, for example, hydrogen and X₂ represents a nucleofugalleaving group. Nucleofugal leaving groups X₂ are, for example,optionally etherified or esterified hydroxy or mercapto groups, and alsoamino, ammonium and sulphonium groups. Etherified hydroxy is, forexample, lower alkoxy, such as methoxy or ethoxy, or optionallysubstituted phenyl-lower alkoxy, such as optionally substitutedbenzyloxy. Esterified hydroxy is especially hydroxy esterified by amineral acid or an organic sulphonic acid, especially halogen, such aschlorine, bromine or iodine, sulphonyloxy, such as optionallyhalosubstituted lower alkanesulphonyloxy, for examplemethanesulphonyloxy or trifluoromethanesulphonyloxy,cycloalkanesulphonyloxy, for example cyclohexanesulphonyloxy, orbenzenesulphonyloxy which is optionally substituted by lower alkyl or byhalogen, for example benzene-, p-bromophenyl- or p-toluene-sulphonyloxy,or also lower alkanoyloxy, for example acetoxy or pivaloyloxy.Etherified mercapto is, for example, lower alkylthio, such as methylthioor ethylthio, or optionally substituted phenylthio, such as phenylthioor p-tolylthio. Esterified mercapto groups are, for example, loweralkanoylthio groups, such as acetylthio. Amino groups are, for example,amino, N-lower alkylamino, N,N-di-lower alkylamino or N-loweralkanoylamino groups, or also lower alkyleneamino or aza-, oxa- orthia-lower alkyleneamino groups, for example dimethylamino ordiethylamino, or pyrrolidino, piperidino, morpholino or thiomorpholino,or also anilino. Ammonium groups are, for example, tertiary orquaternary ammonium groups corresponding to the above-mentioned aminogroups, such as tri-lower alkylammonio or pyridinio. Sulphonium groupsare, for example, di-lower alkylsulphonium groups, such asdimethylsulphonium.

That which has been said for salts and/or tautomers of compounds Iapplies analogously to salts and/or tautomers of compounds II.

The elimination of X₁ and X₂ with the formation of an additional bond(splitting off of X₁ -X₂) is effected in customary manner, for exampleby heating at from approximately 40° to approximately 200° C, and/or, inthe case of compounds II in which X₂ represents hydroxy which isoptionally esterified by a mineral acid or by an organic sulphonic acid,by treatment with a base, or, in the case of compounds II in which X₂represents optionally etherified hydroxy or mercapto, by treatment withan acid. Bases or acids suitable for this are, for example, the basic oracidic agents, respectively, mentioned hereinafter.

The compounds II are preferably manufactured in situ, for example bycyclising a compound of the formula ##STR10## in which X₂ ' representsoptionally functionally modified oxo, or a tautomer and/or salt thereof,the compound II formed as intermediate generally reacting furtheraccording to the invention without being isolated.

Optionally functionally modified oxo X₂ ' is, for example, oxo, thioxoor a group ═N--R₁ ". Groups ═N--R₁ " are, for example, those in which R₁" represents a group R₁ or a group R₁ ' that can be converted into R₁under the reaction conditions, for example the acyl group, for exampleimino, N-lower alkylimino, N-lower alkanoylimino or optionallysubstituted N-benzoylimino.

Tautomers of compounds IIa are, for example, those in which the R_(a)--C(═NR₁)--NH grouping is in protomeric form, i.e. in the form of theR_(a) --C(NHR₁)═N grouping. It is also possible, for example, for acompound IIa containing an oxo, thioxo or imino group X₂ ' to be in itstautomeric form as an enol, en-thiol or enamine of the formula ##STR11##in which X₂ represents hydroxy, mercapto or amino. That which has beensaid for salts of compounds I applies analogously to salts of compoundsIIa or IIb.

The cyclisation of compounds IIa or their tautomers and/or salts and,where appropriate, the subsequent in situ elimination of X₁ -X₂ from theresulting compounds II or, as the case may be, their tautomers and/orsalts are effected in customary manner, i.e. under neutral, acidic orbasic conditions, if necessary in the presence of an acidic or basicagent, in the presence of an inert solvent or diluent or a mixturethereof, at room temperature or, preferably, while heating, for examplein a temperature range of from approximately 40° to approximately 200°C., preferably from approximately 60° to approximately 140° C., and/orunder an inert gas, such as nitrogen.

Suitable acidic agents are, for example, mineral acids or theiranhydrides or acid salts, for example hydrohalic acids, sulphuric acid,alkali metal hydrogen sulphates, phosphoric acid, polyphosphoric acid,phosphorus pentoxide, phosphorus trichloride, phosphorus oxychloride orphosphorus tribromide, organic sulphonic acids, such asp-toluenesulphonic acid, or carboxylic acids or their anhydrides orhalides, such as lower alkanoic acids or their anhydrides or halides,for example acetic acid, acetic anhydride or acetyl chloride, orbuffered acid solutions, for example phosphate or acetate buffer, orhydrohalides of nitrogen bases, for example ammonium chloride orpyridinium chloride.

Basic agents are, for example, hydroxides, hydrides, amides, loweralkoxides, carbonates, di-lower alkylamides or lower alkylsilylamides ofalkali metals or alkaline earth metals, lower alkylamines, basicheterocycles, ammonium hydroxides and carbocyclic amines. Examples thatmay be mentioned are sodium hydroxide, hydride, amide, methoxide,ethoxide or carbonate, potassium hydroxide, tert.-butoxide or carbonate,lithium diisopropylamide, potassium bis-(trimethylsilyl)-amide, calciumhydroxide or hydride, di- or tri-ethylamine, pyridine,benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU).

Inert solvents or diluents that may be mentioned are, for example,halo-lower alkanes, cyclic ethers, aromatic hydrocarbons, N,N-di-loweralkyl-lower alkanoic acid amides, phosphoric acid lower alkylamides,di-lower alkyl sulphoxides and cyclic amines, and also, especially whencarrying out the reaction in the presence of an alcoholate, the alcoholscorresponding to the alcoholate: for example di-, tri- ortetrachloromethane, tetrahydrofuran, dioxan, benzene, toluene, xylene,N,N-dimethylformamide, hexamethylphosphoric acid triamide, dimethylsulphoxide or N-methylmorpholine, and also, for example, methanol,ethanol or tert.-butanol.

The compounds IIa or their tautomers and/or salts can be manufactured,for example, by reacting with each other corresponding compounds of theformulae ##STR12## in which Z₁ represents a nucleofugal leaving groupX₂, X₂ ' represents optionally functionally modified oxo, and Z₂represents hydrazino, or tautomers and/or salts thereof, and canadvantageously be reacted further in situ to form compounds II and I.

For example, compounds IIa in which R_(a) is a group Ph-alk, R_(b) is aradical R₂ and X₂ ' is optionally functionally modified oxo, preferablyoxo, are preferably obtained by reacting with each other correspondingcompounds of the formulae IIc and IId in which Z₁ represents anucleofugal leaving group X₂, preferably lower alkoxy, X₂ ' representsoptionally functionally modified oxo, preferably oxo, and Z₂ representshydrazino, or, as the case may be, their tautomers and/or salts, thereaction preferably being carried out in one of the inert solventsdescribed hereinbefore, while heating, for example in a temperaturerange of from approximately 20° to approximately 200° C., especiallyfrom approximately 40° to approximately 140° C., optionally in thepresence of one of the acidic or basic agents mentioned above and/orunder an inert gas, such as nitrogen. The compounds IIc (R_(a) =Ph-alk,Z₁ =lower alkoxy) are obtained, for example, by reacting aphenylalkanoic acid amide of the formula Ph-alk-CONHR₁ (IIe) with asuitable lower alkylating agent, preferably a tri-lower alkyloxoniumtetrafluoroborate, such as triethyloxonium tetrafluoroborate, forexample in dichloromethane, or by reacting a nitrile of the formulaPh-alk-CN (IIf) with an alcohol in the presence of dry hydrogen chloridegas and optionally converting the resulting iminium hydrochloride intothe free base by treatment with a weak base, such as sodium hydrogencarbonate. The compounds IId (R_(b) =R₂, X₂ '=oxo, Z₂ =hydrazino) areknown or can be manufactured analogously to known methods.

Analogously, compounds IIa in which R_(a) is a group R₂, R_(b) is aradical Ph-alk and X₂ ' is optionally functionally modified oxo,preferably oxo, can be obtained preferably by reacting with each othercorresponding compounds IIc and IId in which Z₁ represents a nucleofugalleaving group X₂, preferably halogen, such as chlorine, X₂ ' representsoptionally functionally modified oxo, preferably oxo, and Z₂ representshydrazino, or, as the case may be, their tautomers and/or salts, thereaction preferably being carried out, for example, while cooling, forexample in a temperature range of from approximately -20° toapproximately +15° C., especially from approximately -5° toapproximately +10° C., in an inert solvent, in the presence of a basicagent and/or under an inert gas, such as nitrogen. The compounds IIc(R_(a) =R₂, Z₁ =halogen) are known or can be obtained analogously toknown methods, for example by reacting optionally N-lower alkyl-,N,N-di-lower alkyl- or N-lower alkanoylsubstituted oxalic acid diamideswith halogenating agents, such as phosgene or phosphorus tribromide. Thecompounds IId (R_(b) =Ph-alk, X₂ '=oxo, Z₂ =hydrazino) are known or canbe manufactured analogously to known methods.

Compounds IIa in which R_(a) is a group R₂, R_(b) is a radical Ph-alkand X₂ ' is optionally functionally modified oxo, preferably oxo, canalso be obtained by first reacting with each other a compound of theformula R₁ N═C(Z₁)--R₂ ' (IIc') in which R₂ ' is, for example, loweralkoxycarbonyl, such as ethoxycarbonyl, or optionally substitutedphenyl-lower alkoxycarbonyl, and Z₁ is a nucleofugal leaving group X₂,preferably halogen, such as chlorine, and a compound IId in which R_(b)represents a radical Ph-alk, X₂ ' represents optionally functionallymodified oxo, preferably oxo, and Z₂ represents hydrazino, or, as thecase may be, a tautomer and/or salt thereof in each case, for exampleunder the reaction conditions indicated above, for example while coolingand/or in the presence of a basic agent, and then, in the resultingcompound of the formula R₂ 'C(═NR₁)--NHNH--C(═X₂ ')alk-Ph (IIa'), or ina tautomer and/or salt thereof which may be obtained, solvolysing thegroup R₂ ' to a carbamoyl group R₂, for example by reaction withammonia, N-mono- or N,N-di-lower alkylamines or N-lower alkanoylamines,advantageously while heating, for example in a temperature range of fromapproximately 30° to approximately 100° C., preferably fromapproximately 40° to approximately 80° C., in the presence of an agentthat removes the elements of water, such asN,N'-dicyclohexylcarbodiimide, and/or under an inert gas, such asnitrogen. The compounds IIc' are known or can be obtained analogously toknown methods, for example in a manner analogous to that described aboveby reacting oxalic acid monoalkyl ester monoamides with halogenatingagents, such as phosgene or phosphorus tribromide.

Analogously, compounds IIa in which R_(a) is a group Ph-alk, R_(b) is aradical R₂ and X₂ ' is optionally functionally modified oxo, preferablyoxo, can also be obtained by first reacting with each other a compoundof the formula H₂ N--NH--C(═X₂ ')--R₂ ' (IId') in which R₂ ' is, forexample, lower alkoxycarbonyl, such as ethoxycarbonyl, or optionallysubstituted phenyl-lower alkoxycarbonyl and X₂ ' is optionallyfunctionally modified oxo, preferably oxo, and a compound IIc in whichR_(a) is a radical Ph-alk and Z₁ is a nucleofugal leaving group X₂,preferably lower alkoxy, or, as the case may be, a tautomer and/or saltthereof in each case, for example under the reaction conditionsindicated above, for example while cooling and/or in the presence of abasic agent, and then, in the resulting compound of the formulaPh-alk--C(═NR₁)--NHNH--C(═X₂ ')--R₂ ' (IIa"), or in a tautomer and/orsalt thereof which may be obtained, solvolysing the group R₂ ' to acarbamoyl group R₂, for example by reaction with ammonia, N-mono- orN,N-di-lower alkylamines or N-lower alkanoylamines under the reactionconditions described hereinbefore. The compounds IId' are known or canbe obtained analogously to known methods.

Compounds IIa in which one of the two radicals R_(a) and R_(b)represents a group Ph-alk and the other represents a radical R₂ and X₂ 'is optionally functionally modified oxo, preferably oxo, can also beobtained by reacting a compound of the formula Ph-alk--C(═X₂ ')NHNHC(═X₂")--Z₃ (IIg) in which each of X₂ ' and X₂ ", independently of the other,represents optionally functionally modified oxo, preferably both oxo,and Z₃ represents either a radical R₂ or a group R₂ ' that can beconverted into a radical R₂, preferably a lower alkoxycarbonyl group,such as an ethoxycarbonyl group, or an optionally substitutedphenyl-lower alkoxycarbonyl group, or, as the case may be, a tautomerand/or salt thereof, with ammonia or with an amine R₁ NH₂,advantageously in the presence of a basic agent, such as pyridine, and,where appropriate, subsequently converting a group R₂ ' into the radicalR₂, for example by solvolysis, for example by reaction with ammonia,N-mono- or N,N-di-lower alkylamines or N-lower alkanoylamines under thereaction conditions described above. The compounds IIg can be obtainedanalogously to known methods, for example by reacting a compound of theformula Z₃ --C(═X₂ ")--NHNH₂ (IId") with a compound of the formulaPh-alk--C(═X₂ ')--Z₁ (IIc") in which Z₁ represents a nucleofugal leavinggroup X₂, preferably lower alkoxy.

In an especially preferred form of process variant a), a compound IIc(R_(a) =Ph-alk, Z₁ =lower alkoxy) is first reacted at from approximately80° to approximately 120° C., for example in N-methylmorpholine orN,N-dimethylformamide, with a compound IId (R_(b) =R₂, X₂ '=oxo, Z₂=hydrazino), the initially formed product IIa (R_(a) =Ph-alk, R_(b) =R₂,X₂ '=oxo) then reacting further in situ to form first the correspondingcompound II (R_(a) =Ph-alk, R_(b) =R₂, X₁ =hydrogen, X₂ =hydroxy) asintermediate, and then, by in-situ-elimination of the elements of water,to yield the corresponding compound of the formula I as end product.

Groups R₂ ' that can be converted according to process variant b) intooptionally N-mono- or N,N-di-lower alkylated or N-lower alkanoylatedcarbamoyl radicals R₂ are either groups R₂ ' that can be solvolysed toradicals R₂ or groups R₂ ' that can be converted into radicals R₂ byoxidation. Groups R₂ ' that can be solvolysed to radicals R₂ arepreferably, for example, free or esterified carboxy groups or carboxygroups in the form of a salt or an anhydride, the cyano group oroptionally lower alkylated or lower alkanoylated amidino groups.

Esterified carboxy groups are, for example, carboxy groups esterified bya lower alkanol or a lower alkyl mercaptan, i.e. lower alkoxycarbonyl orlower alkylthiocarbonyl groups, but may also be esterified by anotheralcohol or mercaptan, for example by an optionally substituted phenol.

Carboxy groups in the form of salts are, for example, carboxy groups inthe form of an ammonium salt derived from ammonia or a mono- or di-loweralkylamine, or carboxy groups in the form of a metal salt, for examplein the form of an alkali metal salt or an alkaline earth metal salt.

Carboxy groups in the form of an anhydride are, for example, carboxygroups in the form of a halide, such as chlorocarbonyl, but may also beanhydridised with a reactive carboxylic acid and be, for example,alkoxycarbonyloxycarbonyl or trifluoroacetoxycarbonyl.

Optionally lower alkylated or lower alkanoylated amidino groups are, forexample, unsubstituted or N-lower alkylated, N,N-di-lower alkylated orN-lower alkanoylated amidino groups.

That which has been said above for salts and/or tautomers of compounds Iapplies analogously to salts and/or tautomers of compounds III.

The conversion of the mentioned groups R₂ ' into carbamoyl that isunsubstituted or substituted as stated is effected in customary manner,for example by solvolysis, that is to say hydrolysis, ammonolysis oraminolysis (reaction with water or ammonia or a mono- or di-loweralkylamine).

By hydrolysis it is possible to convert, for example, unsubstituted orN-mono- or N,N-di-lower alkylated or N-lower alkanoylated amidino groupsR₂ ' into optionally lower alkylated or lower alkanoylated carbamoylgroups, or to convert cyano R₂ ' into carbamoyl. The hydrolysis of thementioned amidino groups is effected, for example, under acidicconditions, for example in the presence of mineral acids, for examplehydrochloric or sulphuric acid. The hydrolysis of cyano is carried out,for example, in the presence of a basic hydrolysing agent, such as analkali metal hydroxide, for example sodium hydroxide solution orpotassium hydroxide solution. It can be facilitated by peroxy compounds,for example hydrogen peroxide, and is effected, for example, in a loweralkanol, for example in ethanol, as diluent.

By ammonolysis or aminolysis it is possible to convert, for example,free or esterified carboxy groups R₂ ' or carboxy groups R₂ ' in theform of a salt or an anhydride into unsubstituted or lower-alkylatedcarbamoyl. If necessary, the operation is carried out in the presence ofa condensation agent, advantageously in an inert solvent. Condensationagents are, for example, basic condensation agents, especially ammoniaor amines used for the aminolysis in excess and, when starting fromcarboxy in the form of an anhydride, also alkali metal hydroxides orcarbonates, or tertiary organic nitrogen bases, such as tri-loweralkylamines or tertiary heteroaromatic nitrogen bases, for exampletriethylamine or pyridine. An especially suitable inert solvent is, forexample, toluene and, in the solvolysis of esterified carboxy groups,also ethanol. Free carboxy groups can be converted into optionally loweralkylated carbamoyl by removing the elements of water from the ammoniumsalts formed as intermediates, for example by heating or by the actionof dehydrating agents, such as by the action of acid anhydrides, forexample phosphorus pentoxide, acetyl chloride and the like, or ofcarbodiimides, for example N,N'-dicyclohexylcarbodiimide.

As a group R₂ ' that can be converted by oxidation into a carbamoylgroup R₂ which is unsubstituted or substituted as indicated there comesinto consideration, for example, the formyl group. The conversionthereof by oxidation is carried out according to customary methods. Forexample, the aldehydes of the formula ##STR13## can be converted intocorresponding compounds I by treatment with ammonia or an N-mono- orN,N-di-lower alkylamine under oxidising conditions, for example in thepresence of oxidising heavy metal compounds, such as manganese(IV),iron(VI) or nickel(IV) compounds or heavy metal peroxides, for examplenickel peroxide. In this conversion, the compounds IIIb are treated, forexample, with dry ammonia gas while cooling, for example in atemperature range of from approximately -60° to approximately ±0° C.,especially from approximately -30° to approximately -15° C., and in thepresence of nickel peroxide, or the aldehyde IIIb is reacted withmanganese dioxide and sodium cyanide in the presence of ammonia or anN-lower alkyl- or N,N-di-lower alkyl-amine, the reaction being carriedout, for example, in isopropanol as solvent and while cooling, forexample in a temperature range of from approximately -20° toapproximately +10° C., especially from approximately -5° toapproximately +5° C.

The starting materials of the formula III in which R₂ ' represents oneof the described radicals that can be converted into R₂ can be obtainedby several methods, for example by eliminating X₁ and X₂, for example ina manner analogous to that described in process variant a), from acompound of the formula ##STR14## in which X₁ and X₂ represent groupsthat can be eliminated with the formation of an additional bond and oneof the radicals R_(c) and R_(d) represents a group and the otherrepresents a radical R₂ ', or, as the case may be, from a tautomerand/or salt thereof. The compounds II' are preferably manufactured insitu, for example by cyclising a compound of the formula ##STR15## inwhich X₂ ' represents optionally functionally modified oxo, or atautomer and/or salt thereof, the cyclisation being carried out in amanner analogous to that described in process variant a). The compoundsII'a can be manufactured, for example, in a manner analogous to thatdescribed in process variant a) for compounds IIa' or IIa".

A further method of manufacturing the starting materials of the formulaIII in which R₂ ' represents one of the described radicals that can besolvolysed to R₂ is based on the introduction of the radical Ph-alk intoa compound of the formula ##STR16## or into a salt thereof, theoperation being carried out in a manner analogous to that described inprocess variant c).

Compounds III which are obtainable in accordance with the process and inwhich R₂ ' represents esterified carboxy or cyano can subsequently behydrolysed, for example by treatment with sodium hydroxide or potassiumhydroxide in aqueous-ethanolic solution, to form the correspondingcarboxylic acids (III; R₂ '=carboxy) which, in a further reaction step,can be converted into the acid chlorides (III; R₂ '=chlorocarbonyl), forexample by means of thionyl chloride in toluene/pyridine or phosphoruspentachloride in tetrahydrofuran or by means of phosphorus oxychloride.Nitriles (III; R₂ '=cyano) formed initially can also be converted byreaction with a mineral acid, for example with hydrochloric orhydrobromic acid or sulphuric acid, and an alcohol, for example a loweralkanol or benzyl alcohol, and further reaction of the resulting iminoether with ammonia or a mono- or di-lower alkylamine, into thecorresponding amidines (III; R₂ '=optionally lower alkylated amidino).

In a preferred embodiment for the manufacture of compounds III in whichR₂ ' is esterified carboxy, compounds of the formulae ##STR17## arereacted with each other in toluene and the resulting initial productIIa' (X₂ '=oxo) is converted in situ, without additional purification,by heating for several hours in boiling xylene, into the correspondingintermediate compound II' (R_(c) =esterified carboxy R₂ ', R_(d)=Ph-alk, X₁ =hydrogen, X₂ =hydroxy), and then, by in-situ-elimination ofthe elements of water, into the desired intermediate III (R₂'=esterified carboxy).

Starting materials III in which R₂ ' represents formyl, i.e. aldehydesIIIb, are also obtainable by oxidation of corresponding primary alcoholsof the formula III (R₂ '=hydroxymethyl), the reaction being carried outunder the customary reaction conditions and using oxidation systems thatare customary for that purpose, such as dimethyl sulphoxide/oxalylchloride, chromium trioxide, sodium dichromate/water, pyridiniumchlorochromate, potassium permanganate, manganese dioxide, bismuthtrioxide, nickel peroxide, ceric ammonium nitrate, leadtetraacetate/pyridine or N-chlorosuccinimide, or using oxygen, forexample in the presence of suitable catalysts, such as metal oxides, forexample aluminium oxide, silicon dioxide or iron(III) oxide, or by meansof dehydrogenating catalysts, such as copper oxide or copper chromite.If nickel peroxide or manganese dioxide are used as oxidising agents,the aldehyde stage does not need to be isolated but can be furtherreacted in situ with ammonia or the corresponding amine. Thecorresponding primary alcohols (III; R₂ '=hydroxymethyl) can beobtained, for example, by reaction of triazoles of the formula ##STR18##with formaldehyde or formaldehyde equivalents, such as paraformaldehyde,in the presence of a basic agent. Suitable basic agents are especiallyorganometal bases, such as alkali metal lower alkyl or alkali metalphenyl compounds, for example methyl- or butyl-lithium or phenyl sodium,which are used while cooling, for example in a temperature range of fromapproximately -100° to approximately +10° C., especially fromapproximately -80° to approximately -20° C., under an inert gas, such asnitrogen, and/or in the presence of an inert solvent, such astetrahydrofuran or 1,2-dimethoxyethane. In a preferred embodiment,gaseous formaldehyde is introduced into the basic reaction mixture. Theprimary alcohols (III; R₂ '=hydroxymethyl) can also be manufactured fromcorresponding compounds II'.

In an alternative procedure, the triazole IIIc can be deprotonated asdescribed and converted by reaction with N,N-di-lower alkylformamides,for example N,N-dimethylformamide, directly into the aldehyde of theformula IIIb.

The triazoles IIIc can be manufactured, for example, by reacting acompound of the formula HalC(═NR₁)H (IIIf) in which Hal representshalogen, such as chlorine, in a manner analogous to that described forcompounds IIc in process variant a), with a compound IId (R_(b) =Ph-Alk,X₂ '=oxo, Z₂ =hydrazino).

The introduction of the radical of the formula Ph-alk into a compound ofthe formula IV (to the salts of which there applies analogously thatwhich has been said above for salts of compounds I) in accordance withprocess variant c) is effected, for example, by reaction with a reactiveester of a corresponding phenyl-lower alkanol that is substituted in thephenyl moiety.

Reactive esters of phenyl-lower alkanols that are substituted in thephenyl moiety have, for example, the formula Ph-alk-Z₄ (IVa), therecoming into consideration as reactive esterified hydroxy Z₄ preferablyhydroxy esterified by a mineral acid or by an organic sulphonic acid,such as hydroxy esterified by a hydrohalic acid or by an aliphatic oraromatic sulphonic acid, for example chlorine, bromine or iodine ormethane-, ethane-, benzene- or p-toluene-sulphonyloxy.

The reaction is carried out, for example, under basic conditions, suchas in the presence of a basic condensation agent, for example of thekind indicated in process variant a), preferably in one of the solventsor diluents that are also indicated there, if necessary while heatingand/or under an inert gas, such as nitrogen.

The compounds of the formula IV are known or can be manufacturedanalogously to known methods, for example by reacting formylhydrazinewith a compound IIc in which R_(a) represents a radical R₂ and Z₁represents a nucleofugal leaving group X₂, preferably halogen, such aschlorine, the customary reaction conditions, for example as described inprocess variant a), being applied.

Groups R₁ ' that are replaceable by hydrogen in accordance with processvariant d) are, for example, acyl groups, for example acyl groupsderived from an organic carboxylic or sulphonic acid.

Acyl derived from an organic carboxylic acid is, for example, theradical of an aliphatic or monocyclic aromatic carboxylic acid, such aslower alkanoyl or optionally substituted benzoyl, also pyridoyl. Acylderived from an organic sulphonic acid is, for example, loweralkanesulphonyl.

That which has been said for salts of compounds I applies analogously tosalts of compounds V.

For the exchange of the acyl group R₁ ' for hydrogen there come intoconsideration the customary reduction systems and reaction conditions,for example diborane, lithium aluminium hydride, sodiumborohydride/cobalt(II) chloride, sodium borohydride/trifluoroacetic acidor trihalosilanes, for example trichlorosilane.

The starting materials V can be obtained, for example, analogously tothe elimination methods described in process variant a). For example, acompound of the formula ##STR19## in which X₂ '" represents a group═N--R₁ ' (R₁ '=acyl) and Z₁ represents a nucleofugal leaving group X₂,for example as described in process variant a), and a compound IId inwhich R_(b) represents a radical R₂, X₂ ' represents optionallyfunctionally modified oxo, preferably oxo, and Z₂ represents hydrazino,or, as the case may be, a tautomer and/or salt thereof in each case, canbe reacted with each other, the initially formed product of the formulaPh-alk--C(═NR₁ ')--NHNHC(═O)R₂ (Vb) then reacting further in situ toform first an intermediate of the formula ##STR20## in which X₁represents hydrogen and X₂ represents hydroxy, and then, byin-situ-elimination of the elements of water, to yield the correspondingcompound of the formula V as end product.

The starting materials of the formula Va can be obtained, for example,by reacting correspondingly N-substituted phenylalkanoic acid amides ofthe formula Ph-alk--C(═O)NHR₁ ' (Vd) with a tri-lower alkyloxoniumtetrafluoroborate, such as triethyloxonium tetrafluoroborate,analogously to the procedure described in process variant a).

In the compounds of the formula VI which are to be used in accordancewith process variant e) (to the salts and/or tautomers of which thereapplies analogously that which has been said above for salts and/ortautomers of compounds I), a radical alk' that can be converted into agroup alk is especially an α-hydroxy-lower alkylidene radical--alk"(OH)-- in which alk" represents a lower alkylidene group that canhave the meanings defined for the group alk in the compounds of theformula I, and, in addition, is substituted by hydroxy at the C-atomlinking the two ring systems. The corresponding compounds of the formula##STR21## in which R₂ represents N,N-di-lower alkylcarbamoyl, such asN,N-dimethylcarbamoyl, are reduced to compounds of the formula Iaccording to the invention by reduction of the hydroxy-lower alkylidenegroup. The customary reaction conditions and reduction systems are usedfor the reduction, for example copper chromite, palladium-on-carbon,lithium aluminium hydride/aluminium chloride, iodine/water/redphosphorus or hydrogen in the presence of catalysts, such as platinum.Two-stage reduction methods also are customary, for example conversionof the alcohol into a sulphonate, for example p-toluenesulphonate, andreduction of the sulphonate in situ, for example with lithium aluminiumhydride in tetrahydrofuran.

The starting materials VIa are obtained, for example, by reacting acompound IV in which R₂ represents N,N-di-lower alkylcarbamoyl, such asN,N-dimethylcarbamoyl, in the presence of a basic agent, for example ofthe kind indicated in process variant a), with an aldehyde of theformula Ph--CHO (VIb), the customary reaction parameters being chosen.

Compounds of the formula I obtainable in accordance with the process orby other means can be converted into other compounds of the formula I byconverting one or more variables of the general formula I into othervariables.

For example, in compounds I, unsubstituted carbamoyl R₂ can be convertedinto N-mono- or N,N-di-lower alkylcarbamoyl, and N-mono-loweralkylcarbamoyl R₂ can be converted into N,N-di-lower alkylcarbamoyl, forexample by treatment with a reactive ester of a lower alkanol, such as alower alkyl halide, for example bromide or iodide, loweralkylsulphonate, for example methanesulphonate or p-toluenesulphonate,or a di-lower alkyl sulphate, for example dimethyl sulphate, preferablyunder basic conditions, such as in the presence of sodium hydride or inthe presence of sodium hydroxide solution or potassium hydroxidesolution and a phase-transfer catalyst, such as tetrabutylammoniumbromide or benzyltrimethylammonium chloride.

Similarly, compounds I in which R₁ represents hydrogen can be N-loweralkylated in analogous manner to compounds I in which R₁ representslower alkyl. The N-alkylation can also be carried out in such a mannerthat when compounds I in which R₁ represents hydrogen and R₂ representsunsubstituted carbamoyl are used as starting material, under thecorresponding reaction conditions, in addition to the introduction ofthe N-lower alkyl group R₁, N-alkylation to N-mono- or N,N-di-loweralkylcarbamoyl R₂ also is achieved in the same reaction step. It ispossible to proceed analogously when compounds I in which R₁ representshydrogen and R₂ is N-mono-lower alkyl-substituted carbamoyl are used asstarting material. According to that method of N-alkylation, compounds Iin which all of the N-lower alkyl groups introduced in the same reactionstep are of the same type are obtained in each case.

It is also possible to convert unsubstituted carbamoyl R₂ into N-loweralkanoylcarbamoyl, for example by reaction with a lower alkanoic acid,such as formic, acetic or propionic acid, or a derivative of such anacid, for example an acid halide, such as an acid chloride, an ester orespecially an anhydride, for example acetyl chloride or aceticanhydride, but it may be necessary to use more strongly basiccondensation agents, such as alkali metal amides or alkali metalalcoholates, for example sodium amide or sodium methoxide, oralternatively acid condensation agents, such as mineral acids, forexample sulphuric acid. Compounds in which R₁ is hydrogen are alsoN-lower alkanoylated at the N⁴ atom during the reaction, so that, whenthe reaction is complete, the lower alkanoyl group must be removed fromthe N⁴ atom in an additional step, for example as described underprocess variant d).

Salts of compounds of the formula I, or, as the case may be, of theirtautomers, can be manufactured in a manner known per se. For example,acid addition salts of compounds of the formula I are obtained bytreatment with an acid or a suitable ion-exchange reagent. The acidaddition salts can be converted into the free compounds in customarymanner, for example by treatment with a suitable basic agent.

Depending on the procedure and reaction conditions, the compounds of theformula I having salt-forming, especially basic, properties, or, as thecase may be, tautomers thereof, may be obtained in free form or in theform of salts.

Owing to the close relationship between the compounds of the formula Iin free form and in the form of their salts, hereinbefore andhereinafter there is to be understood by the free compounds or theirsalts, where appropriate and expedient, also the corresponding salts orthe free compounds, respectively.

The novel compounds of the formula I including their salts in the caseof salt-forming compounds can also be obtained in the form of theirhydrates or can include other solvents, for example solvents used forcrystallisation of compounds that are in solid form.

Depending on the starting materials and procedures chosen, the novelcompounds of the formula I may be in the form of one of the possibleisomers or in the form of a mixture thereof. Depending on the symmetryof the molecule, for example depending on the number and absolute andrelative configuration of the chiral centres, such as asymmetric carbonatoms, it is possible to obtain as pure isomers, for example, pureenantiomers and/or pure diastereoisomers, such as pure cis/transisomers.Correspondingly, isomeric mixtures may be in the form of, for example,enantiomeric mixtures, such as racemates, diastereoisomeric mixtures ormixtures of racemates.

Resulting diastereoisomeric mixtures and mixtures of racemates can beseparated into their components on the basis of the differing physicalproperties of the components by customary physical separating methods,for example by distillation, fractional crystallisation and/orchromatography.

Resulting enantiomeric mixtures, for example racemates, can be resolvedinto the enantiomers according to known methods, for example byrecrystallisation from an optically active solvent, chromatography onchiral adsorbents, with the aid of suitable microorganisms, by cleavagewith specific, immobilised enzymes, by means of the formation ofinclusion compounds, for example using chiral Crown ethers, in whichonly one enantiomer is complexed, or by conversion intodiastereoisomeric salts, for example by reacting a basic end productracemate with an optically active acid, such as a carboxylic acid, forexample tartaric or malic acid, or a sulphonic acid, for examplecamphorsulphonic acid, and separating the mixture of diastereoisomers soobtained, for example on the basis of their different solubilities, intothe diastereoisomers from which the desired enantiomer can then be freedby the action of suitable agents. Advantageously, the more activestereoisomer in each case is isolated.

The invention relates also to those embodiments of the process accordingto which a compound obtainable as an intermediate at any stage of theprocess is used as starting material and the remaining steps are carriedout, or a starting material is used in the form of a derivative or saltand/or in the form of its racemates or enantiomers, or, especially, isformed under the reaction conditions.

The invention relates also to novel starting materials that have beendeveloped specifically for the manufacture of the compounds obtainablein accordance with the process, especially to the preferably usedselection of starting materials that results in the compounds of theformula I characterised as being preferred at the beginning, to theprocesses for their manufacture and to their use as intermediates.

The invention relates also to the use of compounds of the formula I,and, as the case may be, their tautomers and/or pharmaceuticallyacceptable salts, especially as pharmacological active ingredients, moreespecially as pharmacological active ingredients with anti-convulsiveactivity. They can be used, preferably in the form of pharmaceuticalpreparations, in a method for the prophylactic and/or therapeutictreatment of the animal or human body, especially as anti-convulsants,for example for the treatment of convulsions of various origins, forexample for the treatment of epilepsy.

The invention relates also to pharmaceutical preparations that contain acompound of the formula I, or, as the case may be, a tautomer and/orpharmaceutically acceptable salt thereof, as active ingredient, and toprocesses for the manufacture thereof.

The pharmaceutical preparations in question are those which contain atherapeutically effective amount of the active ingredient, optionallytogether with inorganic or organic, solid or liquid pharmaceuticallyacceptable adjuncts, and which are suitable for enteral, for exampleoral, or parenteral administration to warm-blooded animals. For example,pharmaceutical preparations in dosage unit form are preferably used,such as dragees, tablets, capsules or suppositories, also ampoules whichcontain the active ingredient together with diluents, for examplelactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/orglycine, and/or lubricants, for example silica, talc, stearic acid orsalts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol. Tablets may also contain binders, for examplemagnesium aluminium silicate, starches, such as corn, wheat, rice orarrowroot starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired,disintegrators, for example starches, agar, alginic acid or a saltthereof, such as sodium alginate, and/or effervescent mixtures,adsorbents, colourings, flavourings and/or sweeteners. The compounds ofthe formula I can also be used in the form of parenterally administrablepreparations or in the form of infusion solutions. Such solutions arepreferably isotonic aqueous solutions or suspensions, it being possibleto prepare these before use, for example in the case of lyophilisedpreparations which contain the active ingredient on its own or togetherwith a carrier, for example mannitol. The pharmaceutical preparationsmay be sterilised and/or may contain adjuncts, for examplepreservatives, stabilisers, wetting agents and/or emulsifiers,solubilisers, salts for regulating the osmotic pressure and/or buffers.The novel pharmaceutical preparations which, if desired, may containother pharmacologically active substances, are prepared in a mannerknown per se, for example by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes, and contain fromapproximately 0.1% to approximately 100%, especially from approximately1% to approximately 50%, and in the case of lyophilisates up to 100%,active ingredient.

The dosage of the active ingredient may depend upon various factors,such as the method of administration, species of warm-blooded animal,age and/or individual condition. The daily doses to be administered inthe case of oral administration are normally from approximately 5 toapproximately 50 mg/kg and, for warm-blooded animals weighingapproximately 70 kg, are preferably from approximately 0.5 g toapproximately 5.0 g, it being possible advantageously to administerseveral equal partial doses to achieve the daily dosage.

The following Examples serve to illustrate the invention; they are notintended, however, to limit the scope thereof in any way. Temperaturesare given in degrees Celsius.

EXAMPLE 1

320 mg (1.5 mmol) of1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5mmol) of oxalic acid monoamide monohydrazide are dissolved under anitrogen atmosphere in 5 ml of N-methylmorpholine and the whole isheated under reflux for 41 hours. After cooling, the reaction mixture isdiluted with 20 ml of dichloromethane and extracted by shaking insuccession twice with water, twice with 2N hydrochloric acid and againwith water The last three acidic aqueous phases obtained are combined,rendered alkaline with concentrated ammonia solution and extracted threetimes with dichloromethane. The combined organic phases are dried overmagnesium sulphate and concentrated. Recrystallisation of the crudeproduct from ethanol yields 102 mg (27% of the theoretical yield) of thedesired 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamidewhich melts at 189°-190°.

The 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane can bemanufactured, for example, in the following manner:

75.3 g (0.44 mol) of 2,6-difluorophenylacetic acid are dissolved in 96ml (156.5 g; 1.32 mol) of thionyl chloride, stirred for 1 hour at 60°and then heated under reflux for 2 hours. The excess thionyl chloride isthen distilled off and the residue is fractionated, yielding 79.5 g (95%of the theoretical yield) of 2,6-difluorophenylacetyl chloride.

25 ml of methylamine solution (33% in ethanol) are diluted with 90 ml ofdichloromethane. While cooling, 9.52 g (50 mmol) of2,6-difluorophenylacetyl chloride dissolved in 10 ml of dichloromethaneare added dropwise in such a manner that the temperature of the reactionmixture does not exceed 10°. The reaction mixture is stirred for afurther hour at 10° and then extracted three times with water. Theorganic phase is dried over magnesium sulphate and concentrated. Thecrude product is recrystallised from dichloromethane/petroleum ether andyields 8.57 g (92.6% of the theoretical yield) of2,6-difluorophenylacetic acid methylamide of m.p. 163°-164°.

5.55 g (30 mmol) of 2,6-difluorophenylacetic acid methylamide aredissolved in 70 ml of dichloromethane, 7.4 g (39 mmol) oftriethyloxonium tetrafluoroborate are added thereto and the whole isstirred for 25 hours at room temperature. The reaction mixture is thenextracted by shaking in succession with cold 2N sodium carbonatesolution, ice-water and cold saturated sodium chloride solution, driedover magnesium sulphate and concentrated. A mixture of ether and hexaneis added to the residue, the unreacted educt remaining undissolved andbeing filtered off. The filtrate is concentrated and subjected todistillation in a bulb tube. 4 g (62.6% of the theoretical yield) of1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane which boils at70° (0.02 mm) are obtained.

EXAMPLE 2

The reaction of 320 mg (1.5 mmol) of1-ethoxy-2-'(2,6-difluorophenyl)-1-(N-methylimino)ethane and 155 mg (1.5mmol) of oxalic acid monoamide monohydrazide can be carried out, in amanner analogous to that described in Example 1, but using 5 ml ofN,N-dimethylformamide as solvent. 102 mg (27% of the theoretical yield)of 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide ofm.p. 186°-189° are likewise obtained.

EXAMPLE 3

5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide, which meltsat 187°-187.5° (from ethanol), can also be manufactured in a manneranalogous to that described in Examples 1 and 2 by reacting1-ethoxy-2-(o-chlorophenyl)-1-(N-methylimino)-ethane [b.p. 90° (0.02mm)] with oxalic acid monoamide monohydrazide.

EXAMPLE 4

A mixture of 1.85 g (14 mmol) of oxalic acid monoethylamidemonohydrazide and 3 g (14 mmol) of1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)ethane is heated, whilestirring, at 200° (bath temperature) for 45 minutes. After cooling, thereaction mixture is dissolved in dichloromethane. The reaction mixtureis extracted by shaking in succession once with semi-concentratedhydrochloric acid (1 part concentrated hydrochloric acid/1 part water)and twice with 2N hydrochloric acid. The combined aqueous phases areextracted twice with dichloromethane, activated carbon is added theretoand the whole is filtered over Hyflo. The filtrate is rendered alkalinewith concentrated ammonia solution and extracted three times withdichloromethane. The combined organic phases are washed twice withwater, dried over magnesium sulphate, concentrated and crystallised fromdichloromethane/ether. Recrystallisation from ethyl acetate/ether yields5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-(N-ethyl)carboxamideof m.p. 144°-145°.

The oxalic acid monoethylamide monohydrazide can be manufactured, forexample, in the following manner:

7.25 g (50 mmol) of oxalic acid monoethylamide monoethyl ester aredissolved in 70 ml of ethanol. While cooling, 2.5 ml (2.6 g; 52 mmol) ofhydrazine hydrate dissolved in 10 ml of ethanol are added dropwise insuch a manner that the temperature of the reaction mixture does notexceed 10°. The reaction mixture is then stirred for one hour at roomtemperature and the oxalic acid monoethylamide monohydrazide, m.p.161°-164°, which has precipitated is filtered off.

EXAMPLE 5

10 g (36 mmol) of5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acidethyl ester are stirred in 100 ml of 4.4N ammoniacal ethanol for 2 hoursat 70° in a bomb tube. The reaction mixture is then concentrated to halfits volume. The resulting crystals are filtered off, recrystallised fromethanol and yield5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide of m.p.189°-191°.

The 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acidethyl ester can be manufactured, for example, in the following manner:

70.4 g (0.41 mol) of 2,6-difluorophenylacetic acid, 700 ml of ethanoland 35 ml of concentrated sulphuric acid are heated under reflux for 3hours. The reaction mixture is then concentrated by evaporation, takenup in dichloromethane and the solution is extracted by shaking insuccession with water, 2N sodium carbonate solution and again withwater. After drying over magnesium sulphate, the organic phase isconcentrated by evaporation. The residue is dissolved in 560 ml ofethanol. After the addition of 30 ml (31 g; 0.62 mol) of hydrazinehydrate, the whole is heated under reflux for 4 days. After cooling, theresulting crystals are filtered off to yield 56.4 g (74% of thetheoretical yield) of 2,6-difluorophenylacetic acid hydrazide whichmelts at 177°-178°.

18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester aredissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and59 ml of a 20% solution of phosgene in toluene are added thereto. At atemperature of 5°-10°, 9.2 ml of pyridine are added dropwise. Thereaction mixture is then stirred for 2 hours at 0°, nitrogen being blownthrough the reaction mixture during the second hour. 17.6 g (95 mmol) of2,6-difluorophenylacetic acid hydrazide are then added. The reactionmixture is subsequently stirred for 40 minutes at room temperature, thenpoured onto ice-water, acidified with concentrated hydrochloric acid andextracted three times with ether. The acidic aqueous phase is renderedalkaline with concentrated ammonia solution and extracted by shakingthree times with dichloromethane. The combined dichloromethane phasesare washed twice with water, dried over magnesium sulphate andconcentrated by evaporation. The residue is taken up in 160 ml of xyleneand stirred under reflux for 9 hours. The reaction mixture is thenconcentrated and chromatographed over silica gel using ethyl acetate aseluant. The eluate is concentrated by evaporation and the crystallineresidue is recrystallised from ethyl acetate/ether.5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acidethyl ester of m.p. 127°-128° is obtained.

EXAMPLE 6

The following can be manufactured in a manner analogous to thatdescribed in Example 5: from o-fluorophenylacetic acid hydrazide (m.p.139°-143°), phosgene and oxalic acid monomethylamide monoethyl ester,5-(o-fluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethylester (m.p. 83°-84°, from the latter,5-(o-fluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide of m.p.165°-166° and from m-trifluoromethylphenylacetic acid hydrazide (m.p.102°-104°), phosgene and oxalic acid monomethylamide monoethyl ester,4-methyl-5-(m-trifluoromethyl-benzyl)-4H-1,2,4-triazole-3-carboxylicacid ethyl ester (m.p. 64°-65°) and, from the latter,4-methyl-5-(m-trifluoromethylbenzyl)-4H-1,2,4-triazole-3-carboxamide ofm.p. 167°-168°.

EXAMPLE 7

In a manner analogous to that described in Example 5 it is possible tomanufacture from 2,6-difluorophenylacetic acid hydrazide (m.p.177°-178°), phosgene and oxalic acid monoethylamide monoethyl ester,4-ethyl-5-(2,6-difluorobenzyl)-4H-1,2,4-triazole-3-carboxylic acid ethylester (m.p. 120°-121°) and, from the latter,4-ethyl-5-(2,6-di-fluorobenzyl)-4H-1,2,4-triazole-3-carboxamide of m.p.222°-224°.

EXAMPLE 8

In a manner analogous to that described in Example 5 it is possible tomanufacture from5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acidethyl ester (m.p. 127°-128°) also: using methylamine instead of ammonia,5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-(N-methyl)carboxamideof m.p. 179°-180° and, using dimethylamine instead of ammonia,5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-(N,N-dimethyl)carboxamideof m.p. 124°-126°.

EXAMPLE 9

In a manner analogous to that described in Example 5 it is possible tomanufacture from5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethylester, 5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide ofm.p. 187°-187.5°.

The 5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acidethyl ester can be manufactured, for example, in the following manner:

14.8 g (80 mmol) of o-chlorophenylacetic acid hydrazide are suspended in230 ml of dichloromethane. At 5°, 12 g (80 mmol) of2-chloro-2-(N-methylimino)acetic acid ethyl ester [Tetrahedron Lett. 30,2827 (1979)] are added dropwise thereto. The whole is then stirred for 2hours while cooling with ice and then overnight at room temperature. Thereaction mixture is then poured onto ice, 50 ml of 2N hydrochloric acidare added thereto and the whole is extracted twice with dichloromethane.The combined dichloromethane phases are washed twice with water. All theacidic aqueous phases are combined, rendered alkaline with solid sodiumcarbonate and extracted three times by shaking with dichloromethane.These three organic phases are combined, washed in succession with waterand saturated sodium chloride solution, dried over magnesium sulphateand concentrated by evaporation. The residue is taken up in 150 ml ofxylene and stirred under reflux for 44 hours. The reaction mixture isthen concentrated and chromatographed over silica gel using ethylacetate as eluant. The eluate is concentrated by evaporation andrecrystallised from ether.5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethylester of m.p. 87°-88° is obtained in a yield of 12.4 g (55% of thetheoretical yield).

EXAMPLE 10

1.43 g (6 mmol) of5-(2,6-difluorobenzyl)-3-hydroxymethyl-4-methyl-4H-1,2,4-triazole and5.22 g (60 mmol) of manganese dioxide are heated under reflux in 40 mlof toluene for 3 hours using a water separator. The reaction mixture isthen cooled and filtered over Hyflo, and the filtrate is concentrated byevaporation. The residue is added to 90 ml of isopropanol saturated withammonia. At 0°, 1.47 g (30 mmol) of sodium cyanide and 10.44 g (120mmol) of manganese dioxide are added. The reaction mixture is stirredfor 4 hours at 0° and filtered over Hyflo. The filtrate is concentratedby evaporation. Recrystallisation of the residue from ethanol yields thepure 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide.

The 5-(2,6-difluorobenzyl)-3-hydroxymethyl-4-methyl-4H-1,2,4-triazolecan be manufactured, for example, in a manner analogous to thatdescribed in Example 1 or 4 by reacting 2.13 g (10 mmol) of1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane with 0.9 g (10mmol) of hydroxyacetic acid hydrazide.

EXAMPLE 11

70.7 g (300 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-imino-ethanehydrochloride are added, while stirring, to a suspension of 30.9 g (300mmol) of oxalic acid monoamide monohydrazide in 900 ml ofN,N-dimethylformamide. The reaction mixture is heated to 80° and stirredat this temperature for 1 hour. During a period of 20 minutes 10.6 g ofmethylamine are passed into the resulting white suspension, which leadsto the formation of a clear yellow solution. During a period of 1 hour afurther 15.9 g of methylamine are passed into the solution. The solutionis then stirred for another hour at 80°. The solvent is evaporated invacuo. 400 ml of water are added to the residue. The aqueous mixture isstirred and the crystals are filtered off. 300 ml of water are added tothe crystals. The mixture is again stirred and the crystals are filteredoff. The crystals are dissolved in hot ethanol (ca. 500 ml). After theaddition of activated charcoal the mixture is filtered over Hyflo. Thefiltrate is evaporated until crystallisation starts (ca. 230 ml) ofethanol have to be distilled off). The mixture is then cooled in an icebath. The crystals are filtered off and dried overnight in vacuo,yielding the product of example 1.

The 1-ethoxy-2-(2,6-difluorophenyl)-l-imino-ethane hydrochloride can beobtained, for example, as follows: 153 g (1 mol) of2-(2,6-difluorophenyl)acetonitrile are dissolved in a mixture of 116 ml(2 mol) of ethanol and 500 ml of diethyl ether. The solution is cooledto from +5° to +10°. At this temperature 73 g (2 mol) of hydrogenchloride are passed into the solution. The mixture is then left to standfor 2 days at +5°. The resulting crystals are filtered off and washedwith diethylether. After recrystallisation from ethanol/diethyl etherthe crystals are dried overnight in vacuo, yielding the desired startingmaterial.

EXAMPLE 12

The following compounds can also be manufactured in a manner analogousto that described in Examples 1 to 11:

5-(o-chlorobenzyl)-1,2,4-triazole-3-carboxamide, m.p. 208°-214°,

5-(2,6-difluorobenzyl)-1,2,4-triazole-3-carboxamide, m.p. 203°-204°,

5-[1-(2,6-difluorophenyl)ethyl]-4-methyl-4H-1,2,4-triazole-3-carboxamide,and

5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-(N-acetyl)-carboxamide.

EXAMPLE 13

Tablets, each containing 50 mg of active ingredient, for example5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide, can bemanufactured, for example, as follows:

COMPOSITION (FOR 10,000 TABLETS)

active ingredient 500.0 g

lactose 500.0 g

potato starch 352.0 g

gelatine 8.0 g

talc 60.0 g

magnesium stearate 10.0 g

silica (highly dispersed) 20.0 g

ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potatostarch, and the mixture is moistened with an alcoholic solution of thegelatine and granulated through a sieve. After drying, the remainder ofthe potato starch, the talc, magnesium stearate and the highly dispersedsilica are admixed and the mixture is compressed to form tablets eachweighing 145.0 mg and containing 50.0 mg of active ingredient, which, ifdesired, may be provided with dividing notches for finer adjustment ofthe dosage.

EXAMPLE 14

Lacquer-coated tablets, each containing 100 mg of active ingredient, forexample5-(2,6-di-fluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide, can bemanufactured, for example, as follows:

COMPOSITION (FOR 1000 TABLETS)

active ingredient 100.00 g

lactose 100.00 g

corn starch 70.00 g

talc 8.50 g

calcium stearate 1 50 g

hydroxypropylmethylcellulose 2.36 g

shellac 0.64 g

water q.s.

dichloromethane q.s.

The active ingredient, the lactose and 40 g of the corn starch aremixed, moistened with a paste prepared from 15 g of corn starch andwater (while heating) and granulated. The granulate is dried, and theremainder of the corn starch, the talc and the calcium stearate areadded and mixed with the granulate. The mixture is compressed to formtablets (weight 280 mg) and these are coated with a solution of thehydroxypropylmethylcellulose and the shellac in dichloromethane; finalweight of a lacquer-coated tablet 283 mg.

EXAMPLE15

In a manner analogous to that described in Examples 13 and 14 it ispossible to manufacture also pharmaceutical preparations containing adifferent compound of the formula I or, as the case may be, a tautomerand/or a pharmaceutically acceptable salt thereof, for example inaccordance with Examples 1 to 12.

I claim:
 1. Method for the treatment of convulsions characterised inthat an anti-convulsively effective amount of a compound of the formula##STR22## in which Ph represents phenyl substituted by lower alkyl,halogen and/or by trifluoromethyl, alk represents lower alkylidene, R₁is lower alkyl, and R₂ represents carbamoyl that is unsubstituted or issubstituted by lower alkyl or by lower alkanoyl, in each case in freeform or in form of a pharmaceutically acceptable salt, is administered asubject in need of such treatment.
 2. Method for the treatment ofconvulsions comprising administering to a warm blooded animal in needthereof an anti-convulsively effective amount of a compound of theformula I according to claim 1, with the proviso that, in a compound ofthe formula I in which R₁ represents methyl, R₂ representsN,N-diethylcarbamoyl and alk represents methylene, Ph is other thanphenyl substituted in the p-position by chlorine, in free form or inform of a pharmaceutically acceptable salt.
 3. Method for the treatmentof convulsions according to claim 2 comprising administering a compoundof formula I in which Ph represents phenyl mono-, di- or tri-substitutedby lower alkyl, halogen and/or by trifluoromethyl, alk represents loweralkylidene, R₁ is lower alkyl, and R₂ represents carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl or N-loweralkanoylcarbamoyl, in free form or in form of a pharmaceuticallyacceptable salt.
 4. Method for the treatment of convulsions according toclaim 2 comprising administering a compound of formula I in which Phrepresents phenyl mono-substituted by C₁ -C₄ -alkyl, halogen or bytrifluoromethyl or di-substituted by halogen and C₁ -C₄ -alkyl, or byhalogen or by halogen and trifluoromethyl, wherein halogen in each casehas an atomic number of up to and including 35, alk represents 1,1- or2,2-C₁ -C₄ -alkylidene, R₁ is C₁ -C₄ -alkyl, and R₂ representscarbamoyl, N-C₁ -C₄ -alkylcarbamoyl, N,N-di-C₁ -C₄ -alkylcarbamoyl orN-C₂ -C₇ -alkanoylcarbamoyl, in free form or in form of apharmaceutically acceptable salt.
 5. Method for the treatment ofconvulsions according to claim 2 comprising administering a compound offormula I in which Ph carries at least a lower alkyl or a halogensubstituent in an o-position or a trifluoromethyl substituent in am-position, in free form or in form of a pharmaceutically acceptablesalt.
 6. Method for the treatment of convulsions according to claim 2comprising administering a compound of formula I in which Ph representso-C₁ -C₄ -alkylphenyl, m-trifluoromethylphenyl, o-halophenyl or 2,3-2,4-, 2,5- or 2,6-dihalophenyl, wherein halogen in each case has anatomic number of up to and including 35, alk represents 1,1-C₁ -C₄-alkylidene, R₁ is C₁ -C₄ -alkyl, and R₂ represents carbamoyl or N-C₁-C₄ -alkylcarbamoyl, N,N-di-C₁ -C₄ -alkylcarbamoyl or N-C₂ -C₇-alkanoylcarbamoyl, in free form or in form of a pharmaceuticallyacceptable salt.
 7. Method for treatment of convulsions according toclaim 2 comprising administering a compound of formula I in which Phrepresents m-trifluoromethylphenyl, o-fluorophenyl or2,6-difluorophenyl, alk represents methylene, R₁ is C₁ -C₄ -alkyl, andR₂ represents carbamoyl, in free form or in form of a pharmaceuticallyacceptable salt.
 8. Method for the treatment of convulsions according toclaim 2 comprising administering a compound of formula I in which Phrepresents m-trifluoromethylphenyl or 2,6-difluorophenyl, alk representsmethylene, R₁ is C₁ -C₄ -alkyl, and R₂ represents carbamoyl, in freeform or in form of a pharmaceutically acceptable salt.
 9. Method for thetreatment of convulsions according to claim 2 comprising administering5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide or apharmaceutically acceptable salt thereof.
 10. Method for the treatmentof convulsions according to claim 2 comprising administering5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide or apharmaceutically acceptable salt thereof.
 11. Method for the treatmentof convulsions according to claim 2 comprising administering5-(o-fluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide or apharmaceutically acceptable salt thereof.
 12. Method for the treatmentof convulsions according to claim 2 comprising administering4-methyl-5-(m-trifluoromethylbenzyl)-4H-1,2,4-triazole-3-carboxamide ora pharmaceutically acceptable salt thereof.
 13. Method for the treatmentof convulsions according to claim 2 comprising administering4-ethyl-5-(2,6-difluorobenzyl)-4H-1,2,4-triazole-3-carboxamide or apharmaceutically acceptable salt thereof.
 14. Method for the treatmentof convulsions according to claim 2 comprising administering5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-(N-methyl)-carboxamideor a pharmaceutically acceptable salt thereof.
 15. Method for thetreatment of convulsions according to claim 2 comprising administering5-[1-(2,6-difluorophenyl)-ethyl]-4-methyl-4H-1,2,4-triazole-3-carboxamideor a pharmaceutically acceptable salt thereof.
 16. Method for thetreatment of convulsions according to claim 2 comprising administering5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-(N-acetyl)carboxamideor a pharmaceutically acceptable salt thereof.
 17. Method for thetreatment of convulsions according to claim 1 wherein the convulsionsare due to epilepsy.